It is known that ethyl-3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionate having the INN dabigatran etexilate of the Formula
is an oral anti-coagulant of a thrombine inhibitory mechanism.
Dabigatran etexilate was first described by Hauel et al in EP 966 454 (Hungarian equivalent HU 223 754). The dabigatran etexilate base of the Formula 1 is prepared by the synthesis route shown on reaction scheme 1. In the last step the hydrochloride salt of the amidine of the Formula
is coupled with the hexyl chloro formiate of the Formula

The key step of the synthesis route is the conversion of the nitrile of the Formula
into the amidine/2XHCl//Pinner reaction/. The low yields of the Pinner reaction can be derived from the water sensibility of the reaction on the one hand while the realization of the reaction is rendered more difficult on the other by the fact that the ester function of the molecule is susceptible to hydrolysis. According to Example 58b of said patent—in an analogous manner to Example 25d 1.2 g of 1-methyl-2-[N-(cyanophenyl)-aminomethyl]-5-benzimidazole-carboxylic acid-N-(2-pyridyl)-N-[2-(ethoxycarbonylethyl]-amide (4) is reacted with ethanol saturated with hydrochloric acid in large dilution. The evaporated crude product is then converted with 100 ml of ethanol and ammonium carbonate into the hydrochloric acid salt of 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-5-benzimidazole-carboxylic acid-N-(2-pyridyl)-N-[2-(ethoxycarbonyl)-ethyl]-amide (2). Said compound is purified by repeated removal of the solvent and column chromatography. The base thus obtained (1) is characterized only by TLC Rf value and mass chromatography data. Thus it does not appear whether the product is crystalline or amorphous.
                The synthesis route of dabigatran etexilate according to the basic patent is shown on reaction scheme 1.        
The purification step performed by using large dilutions and column chromatography makes the scaling up and industrial scale realization of the process impossible or strongly limited. According to Example 113 the last step (2XHCl to 1) is carried out by coupling 1-methyl-2-[N-(4-amidino-phenyl)-aminomethyl]-5-benzimidazole-carboxylic-acid-N-(2-pyridyl)-N-[2-(ethoxycarbonyl-ethyl]-amide (2XHCl) and hexyl chloro formiate (3). The total yield of the process/5→1/is only 22%, related to the 3-amino-4-(methylamino-benzoic) acid-N-[2-/ethoxycarbonyl-ethyl]-amide (5) starting material.
In their article (J. Med. Chem. 2002, 45, 1757-1766) Hauel et al describe a process identical with that set forth in the basic patent but the preparation of the coupling agent (5) is explained in details on reaction scheme 2. via the amino-nitro compound of the Formula

The dabigatran etexilate base/1/is characterized by mass spectrum, 1H NMR and melting point (128-129° C.). The latter value is identical with that indicated later for the anhydrous III modification (WO 2008/059029 Tmp=128±3° C.).
The broadened synthesis route of dabigatran etexilate is shown on reaction sequence 2 (J. Med. Chem. 2002, 45, 1757-1766).

A new synthesis route of dabigatran etexilate is disclosed in WO 2006/000353. The steps of the synthesis are shown on reaction sequence 3. This synthesis route contains more steps than the process described in the basic patent. According to Examples 1 and 2 the 2-[4-(1,2,4-oxadiazole-5-on-yl)-phenylamino]acetic acid of the Formula
is prepared in several steps; said compound contains the necessary amidino group in a cyclic form. This compound is coupled with 3-amino-4-(methylamino)-benzoic acid-N-[2-(ethoxycarbonyl-ethyl]-amide (5) according to the method described in the basic patent. In Example 3 the coupling step is described in three variants (A. B C) to yield the diacetate salt of 1-methyl-2-{N-[4-(1,2,4-oxadiazole-5-one-3-yl)-phenyl]-amino/methyl}-benzimidazole-5-yl-carboxylic acid-N-(2-pyridyl/-N-[2-(ethoxycarbonyl-ethyl]-amide of the Formula

In the coupling reaction 1,1′carbonyl-diimidazole (CDI), triproplyl-phosphonic acid anhydride (T3P) or pivaloyl chloride is used as auxiliary reactant. From the diacetate salt of (8) by hydrogenation and addition to the crude product an excess of p-toluenesulfonic acid the tosylate salt of 1-methyl-2-[N-(4-amidino-phenyl)-aminomethyl]-5-benzimidazole-carboxylic acid-N-(2-pyridyl)-N-[2-(ethoxy-carbonyl)-ethyl]-amide (2) is obtained. In Examples 4A, 4B and 4C a base:acid ratio of 1:1 is stipulated for this product. The latter tosylate salts are characterized by melting point (DSC) and purity (HPLC) and from these measurements one can not conclude to the base:acid ratio.
                The new synthesis route of dabigatran etexilate according to WO 2006/000353 is shown on reaction scheme 3.        
According to WO 2006/000353 dabigatran etexilate (1) is prepared as described in Examples 5A and 5B by reacting the tosylate salt (2Xp-TsOH) and hexyl chloro formiate (3) in an acetone-aqueous medium. The product dried at 45° C. is not characterized by any analytical data. On the basis of the calculations the product is presumed to be anhydrous.
The diacetate structure (8) of the starting material of the hydrogenation (polyvalent base) shows that the product formed (2) will also be capable of binding more than one acids. This is substantiated by a subsequent patent application (WO 2010/045900, reaction sequence 7, 2X2HCl).
On repeating the experiments in our laboratory in accordance with examples 4A, 4B and 4C we obtained tosylate salts of non-stoichiometrical composition. In the latter case the base:acid ratio was 1:(1.6-1.8) and this is in conformity with the fact that in said examples p-toluenesulfonic acid monohydrate was used in a 1.6-fold excess. For this reason the actual yield of the process (8X2AcOH to 2X1.8p-TsOH) is significantly lower than that given in said international patent application.
According to WO 2006/000353 dabigatran etexilate (1) is prepared by crystallization from an acetone/water system (see/Example 5A) and in said process no drying agent or other dehydrating agent is used.
In a later International application (WO 2006/131491, Example 3) originator described the tetrahydrate form dabigatran etexilate (1) which was prepared by carrying out crystallization from an acetone-water mixture as well. Thus it is highly probable that the precipitation of the anhydrous base from an acetone-water mixture or from another water-containing mixture is not at all likely and can not be expected with a reasonable possibility.
We have also repeated Example 5A of WO 2006/000353 and failed to obtain anhydrous dabigatran etexilate (1) but rather the modification thereof containing four moles of water. The correction of the molecular weight to the water containing base results in a lower yield for this process too (2Xp-TsOH→1X4H2O).
The three modifications of the dabigatran etexilate (1) base—two anhydrous and the tetrahydro form—are described by Hauel et al in WO2006/131491. In this international patent application no process is disclosed for the preparation of 1 but reference is made rather to the basic patent. For this reason said new forms are obtained by recrystallization of a modification of unknowns structure from ethyl acetate (anhydrous form I and anhydrous form II; Examples 1 and 2) and a mixture of acetone and water (tetrahydrate form, Example 3), respectively.
In WO 2007/1742 one-pot procedures are protected by combining two different steps each described in earlier WO 2006/000353. The steps of the process are shown on reaction scheme 4. In one of said reaction routes dabigatran ethexylate (1) base is prepared by hydrogenating the intermediate (8X2AcOH) containing the oxadiazole ring rather than by preparing the tosylate salt of the benzamidine derivative (2). The catalyst is filtered off and acylation is carried out in a mixture of acetone and water at 15° C. without isolating the reduced product (2). The dabigatran etexilate (1) base is not characterized but the calculations are related to the anhydrous form. The base (1) is converted into the mesylate salt (1XMsOH) by reacting with methanesulfonic acid. According to Example 7 in the base synthesis the product (1) is recovered from a mixture of acetone and water without including a dehydrating step. Taking into consideration Example 3 of WO 2006/131491 the formation of the anhydrous product can not be expected. The yield corrected to the molecular weight of dabigatran etexilate (1) tetrahydrate is decreased in this case as well. (8X2AcOH→1X4H2O).
                The synthesis routes of dabigatran etexilate (1) according to WO 2007/071742 are shown on reaction scheme 4.        
In WO 2007/007142 three further variants are disclosed for the preparation of dabigatran etexilate (1) starting from the tosylate salt of the amidine (2); said procedures differ from each other in the reaction conditions and the method of working up. Thus Example 6A is identical with Example 5A of WO 2006/000353, however in the working up method of new variants 6B and 6C an azeotropic distillation is applied dehydration step. Accordingly in these cases actually the anhydrate of dabigatran etexilate (1) is formed and consequently the yield is lower (2*p-TsOH→1).
According to an other process of WO 2007/071742 (reaction scheme 4) the benzamidine derivative (2) is obtained after hydrogenation in the form of the tosylate salt, whereupon the dabigatran etexilate (1) formed in course of the acylation is not isolated from the reaction mixture but is used in the one-pot synthesis to yield the mesylate salt (1XMsOH). In this case the tosylate salt of the amidine (2) is not characterized either but in the calculations it is presumed to be the monotosylate. On the basis of the indicated values the mesylate salt of the end-product (1) is obtained with a total yield of 79-81%, starting from the coupled oxadiazolone (8X2AcOH) derivative (8X2AcOH→1XMsOH). The purity of the product is 99%.
Thus according to the reaction variant described in WO/2007/071742 the mesylate salt of the end-product (1) is prepared with a lower total yield when starting from the coupled oxadiazolone derivative (8*2AcOH→1*MsOH). A further significant drawback of the process is that no purification step is used during the preparation of the mesylate salt of the end-product (1). The indicated HPLC purity (>99%) is per se insufficient to meet the strong purity requirements of internationally accepted ICH Directives defined for pharmaceutical active ingredients by pharmaceutical monograph. Accordingly the amount of identified impurities can not exceed 0.15% and that of the unidentified impurities 0.10%. The HPLC method provides no information about the possible inorganic impurities of the active ingredient. The latter phenomenon can easily appear in course of crystallization by precipitation following the combination of several steps. A further disadvantage resides in the fact that while several methods are disclosed for the recrystallization (purification) of the base (1) (see WO 2006/000353, Example 5A; WO 2005/028468 Example 1-5), no procedures are known for the recrystallization of the mesylate salt of the end product (1*MsOH). Since the reliable fulfilment of the above criteria requires the insertion of at least purification step/s/into the manufacturing procedure, the above process is unable to guarantee the purity of the end product.
WO 2007/0718743 is practically an extension of WO 2007/071742; on carrying out the one pot synthesis route from the components of the coupling step (5,7) via the crude product of the hydrogenation (8*2AcOH), the process is continued as far as the mesylate salt of dabigatran etexilate (1). The HPLC purity (higher than 99%) of the product of the process (5→1*MsOH) is per se insufficient to comply with the severe purity requirements of pharamacopoeia. The process fails to use a purification step and this is a drawback. On combining more steps the risk of the appearance of contaminating impurities is significantly increased and said impurities can in optimal cases be removed from the active ingredient by means of recrystallization. In said process the end product is obtained by combining three steps but without including a purification step; according to our best knowledge the final recrystallization step is not settled yet and therefore the quality of the ends product can not be warranted.
A new variant of the extended basic patent (reaction scheme 2) is disclosed in WO 2009/111997. (reaction scheme 5). The preparation of the diamine derivative (5) is not carried out by catalytic hydrogenation of the nitro derivative (6), reaction scheme 2) but by sodium dithionite reduction of the hydrochloride salt of the nitro derivative (6*HCl). The compound (5) is coupled to the benzimidazole derivative (4) by known methods. Said intermediate is converted into the oxalate salt (4*(COOH)2). In accordance with the basic patent the further steps of the synthesis of dabigatran etexilate (1) start from said oxalate salt. However these steps are not supported by examples and therefore no yields are known.
                Reaction variant 5: Synthesis route of the intermediates of dabigatran etexilate (1) according to WO 2009/111997.        
Taking into consideration the process of the originator described in WO 2006/000353 said reaction route according to WO 2009/111997 can not be regarded as economical
Also in WO 2009/153214 a modified variant of the extended basic patent synthesis (reaction variant 2) is set forth. In this WO an improved process is reported for the reduction of the methylamino-nitro derivative (6). On performing the catalytic reduction of the nitro group both the utilization of the catalyst and the yield of the product (5) are improved.
In WO 2009/153215 a further one-pot embodiment of the synthesis route according to reaction scheme is disclosed. Thus the tosylate salt of the amidine (2) is prepared in a one-pot process starting from the phase products (5,7) obtained before the coupling step (reaction scheme 6). After the coupling reaction the non-isolated oxadiazole derivative (89 obtained is hydrogenated in the presence of ammonia and p-toluenesulfonic acid to yield the desired tosylate salt (5→2*p-TsOH). The tosylate salt formed is only characterized by HPLC data and the calculations infer a monotosylate structure.
                Reaction scheme 6: Synthesis route of the intermediate of dabigatran etexilate (1) according to WO 2009/153215        
An article published in 2009 (UP. Com. Journal 2009, 9, 20) reports a detailed process for the realization of the Pinner-reaction mentioned in the basic patent. Hydrolysis of the nitrile derivative (4) is carried out at room temperature with the aid of an approximately 100 molar amount of hydrochloric acid. Thus the end product (2*HCl) is obtained in an appropriate purity by five recrystallization steps. The hydrochloride of the amidine product (2) is characterized only by X-ray powder diagram. The low yield, the high dilution ratio and the difficulties of the purification step make said process unsuitable for industrial scale manufacture.
WO 2010/045900 provides a discussion of the modified basic patent route (reaction scheme 2). This international patent publication is essentially a continuation of an earlier international patent application of the authors (WO 2009/111997, reaction scheme 5). According to reaction scheme 7 the inventors started from the oxalate salt of the nitrile compound (4) and prepared the dabigatran etexilate (1) base via two new intermediate salt forms (monohydrochloride ethanolate and dihydrochloride) of the amidine (2).
                Reaction scheme 7: Synthesis route of dabigatran etexilate (1) according to WO 2010/0459000        
The base (1) is prepared with low yield by a process starting from the diamine (5) derivative and completed by the reaction sequence shown on reaction schema 5 and 7. This process is not economical.